Hydrogen peroxide metabolism and sensing in human erythrocytes: A validated kinetic model and reappraisal of the role of peroxiredoxin II
Hydrogen peroxide metabolism and sensing in human erythrocytes: A validated kinetic model and reappraisal of the role of peroxiredoxin II
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DOI：
10.1016/j.freeradbiomed.2014.06.007
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发表时间：
2014-09-01
影响因子：
7.4
通讯作者：
Salvador, Armindo
中科院分区：
文献类型：
--
作者：
Benfeitas, Rui;Selvaggio, Gianluca;Salvador, Armindo
过氧化氢（H2 O2）在人体红细胞中的代谢已被彻底研究，但仍存在不明确的点。通过将现有数据整合到一个精确代表当前理解的数学模型中，并将计算预测与观察结果进行比较，我们试图（a）识别现有知识中的不一致性，（B）提出解决方案，（c）检查其功能含义。完整红细胞反应的实验观察与计算预测的系统对抗突出了以下重要的差异。对于纯化的过氧化物氧还蛋白II（Prx 2）测定的H2 O2还原的高速率常数（10（7）-10（8）M-1 s（-1））和该蛋白的高丰度表明，在生理条件下，它几乎消耗所有的H2 O2。然而，这与大量证据不一致，即Prx 2对H2 O2消除的贡献与过氧化氢酶相当。修改后的模型使得Prx 2的有效过氧化物酶活性仅为10（5）M-1 s（-1），与广泛的实验观察结果在数量上接近一致。这种低有效活性可能是由于在完整细胞中Prx 2的过氧化物活性的强烈但容易可逆的抑制，这意味着Prx 2在人红细胞中的主要作用不是消除过氧化物底物。对生理H2 O2刺激的响应的模拟强调了将丰富的Prx 2与低有效过氧化物酶活性相结合的设计在改善Prx 2/硫氧还蛋白/硫氧还蛋白还原酶系统的潜在信号传导特性的同时节省NADPH。(C)2014年爱思唯尔公司All rights reserved.
Hydrogen peroxide (H2O2) metabolism in human erythrocytes has been thoroughly investigated, but unclear points persist. By integrating the available data into a mathematical model that accurately represents the current understanding and comparing computational predictions to observations we sought to (a) identify inconsistencies in present knowledge, (b) propose resolutions, and (c) examine their functional implications. The systematic confrontation of computational predictions with experimental observations of the responses of intact erythrocytes highlighted the following important discrepancy. The high rate constant (10(7)-10(8) M-1 s(-1)) for H2O2 reduction determined for purified peroxiredoxin II (Prx2) and the high abundance of this protein indicate that under physiological conditions it consumes practically all the H2O2. However, this is inconsistent with extensive evidence that Prx2's contribution to H2O2 elimination is comparable to that of catalase. Models modified such that Prx2's effective peroxidase activity is just 10(5) M-1 s(-1) agree near quantitatively with extensive experimental observations. This low effective activity is probably due to a strong but readily reversible inhibition of Prx2's peroxidatic activity in intact cells, implying that the main role of Prx2 in human erythrocytes is not to eliminate peroxide substrates. Simulations of the responses to physiological H2O2 stimuli highlight that a design combining abundant Prx2 with a low effective peroxidase activity spares NADPH while improving potential signaling properties of the Prx2/thioredoxin/thioredoxin reductase system. (C) 2014 Elsevier Inc. All rights reserved.